We are seeking continued funding to ask a number of questions about strategies to mature the fetal lung that have the potential to be applied clinically. We hypothesize that single dose, direct fetal administration of hormones alone or in combination will cause rapid and large lung maturational effects in fetuses that have not been previously manipulated. We plan to use hormones (corticosteroids, thyroid hormones, EGF and TGF-alpha) only at doses and treatment durations that are clinically relevant. We will treat preterm sheep by ultrasound guided direct fetal injections and then deliver the preterm lambs 48 hours later. The lambs will be evaluated extensively for postnatal pulmonary adaptation over 4 hours. Physiologic assessments will focus on measurements that translate into improved lung function. We will measure lung volumes, compliances, gas exchange, edema formation, and the responses of the lungs to surfactant treatment. We also will measure biochemical markers of lung maturation - alveolar and lung tissue saturated phosphatidylcholine pool sizes, alveolar surfactant protein A (SP-A), and SP-A, SP-B, and SP-C mRNA levels in lung tissue. The goal is to identify a simple, single dose treatment strategy that can include agents not permeable to the placenta that will effectively and reliably mature the fetal lung.
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